Phenoxypropylamines in compositions and methods for effecting b-sympatholytical activity

ABSTRACT

PHARMACEUTICAL COMPOSITIONS CONTAINING ALOXYTHIOPHENOXY N SUBSTITUTED HYDROXY-PROPYLAMINO-PROPANES. THE COMPOSITIONS ARE USEFUL IN TREATING DISESASES REQUIRING USE OF AGENTS EXHIBITING B-SYMPATHOLYTICAL ACTIVITIES.

United States Patent 3,632,780 PHENOXYPROPYLAMINES IN COMPOSITIONS ANDMETHODS FOR EFFECTING B-SYM- PATHOLYTlCAL ACTIVITY Volkert Govert Keizerand Johannes Maria Antonius Zwagemakers, van Houtenlaan, Weesp,Netherlands, assignors to U.S. Philips Corporation, New York, N .Y. NoDrawing. Original application Mar. 22, 1966, Ser. No. 536,320, nowPatent No. 3,542,874, dated Nov. 24, 1970. Divided and this applicationNov. 24, 1969, Ser. No. 877,592 Claims priority, applicationNetherlands, Apr. 3, 1965, 6504268 Int. Cl. A61k 27/00 U.S. Cl. 424-33014 Claims ABSTRACT OF THE DISCLOSURE Pharmaceutical compositionscontaining aloxythiophenoxy N substituted hydroxy-propylamino-propanes.The compositions are useful in treating disesases requiring use ofagents exhibiting fl-sympatholytical activities.

This application is a division of applicants copending U.S. Patentapplication No. 536,320, tiled Mar. 22, 1966 and now U.S. Pat. No.3,542,874.

The invention relates to novel phenoxypropylamines, to pharmaceuticalpreparations containing said phenoxypropylarnines and to methods ofproducing and utilizing said phenoxypropylamines and preparations.

A principal object of our invention is to produce a new and novel groupof compounds exhibiting ,B-sympatholytical activities.

Another object of our invention is to provide a new and novel method oftreating fi-sympathomimetic disturbances in mammals.

These and other objects of our invention will be apparent from thedescription that follows:

From the Irish patent application 900/ 64 it is known that compounds ofthe Formula I:

( OH H CH3 wherein R may designate a halogen atom, a branched orstraight chain alkylor alkoxy group having 1 to 4 carbon atoms and x mayhave the value 1, 2 or 3, have a strong B-sympatholytical activity.

According to our invention we have prepared a new and novel group ofcompounds of the formula:

i OH H Sn wherein R is alkyl of 1 to 4 carbon atoms inclusive and R is amember selected from the group consisting of alkyl of 1 to 12 carbonatoms inclusive, alkenyl of 2 to 12 carbon atoms inclusive, alkinyl of 2to 12 carmon atoms inclusive, cycloalkyl of 2 to 12 carbon atomsinclusive and aralkyl of 7 to 12 carbon atoms inclusive and thepharmaceutically acceptable acid addition salts thereof.

We have found unexpectedly that the fl-sympatholytical activities ofthese compounds are significantly greater than the compounds of saidIrish patent.

This definition of the compounds according to the invention includesboth the stereoisomers and mixtures thereof.

R may represent for example methyl, ethyl, n.propyl i.propyl orsec.butyl among others. R may represent ice such alkyls as methtyl t.butyl, hexyl, nonyl or dodecyl, such akenyl groups as allyl, vinyl,pentenyl or decenyl as well as many others. R when al-kinyl, mayrepresent propinyl, ethinyl, hexinyl, among others, R when cycloalkyl,may represent cyclopropyl, cyclopentyl, cyclohexyl or cyclooctyl, amongothers. Also, R when aralkyl, may represent benzyl, phenylpropyl,phenylbutyl or phenylpentyl, among others.

The compounds according to the invention have very eifectiveB-adrenergetically blocking properties and are strong antagonists ofB-sympathicomimetica, for example N-isopropylnoradrenaline.

Owing to these properties the compounds may be employed, when suitablyprepared for administration, :for suppressing or preventing tachycardiacaused by ,B-sympathicomimetica. They may furthermore be used fortreating certain forms of hypertension, angina pectoris, heartarhythmia, digitalis poisoning and phaeochromocytoma.

An important property of the compounds according to the invention isthat they are only very slightly toxic for warm-blooded animals. With1-(2-methylthiophenyl)- 2-hydroxy 3-i.propylaminopropane for example anLD of 126 mg./kg. i.p. and 348 mg./kg. oral has been assessed,

In accordance with the nature and the gravity of the illness to betreated, the compounds may be administered in a daily dose of about 20to about 400 mgs. This quantity may be administered in one batch or in anumber of portions. It will, in general, not be diflicult for thephysician to prescribe the correct quantity and the correct schedule ofadministration.

Administration may be carried out orally, rectally by means ofsuppositories or parenterally.

Examples of the compounds according to the invention are:

1- 2-methylthiophenoxy) -2-hydroxy-3-t. butylaminopropane,

1- Z-methylthiophenoxy) -2-hydroxy-3- 1-methyl-3- phenylpropylamino-prop ane,

1- Z-methylthiophenoxy) -2-hydroxy-3-cyclopentylaminopropane,

1- (Z-ethylthiophenoxy) -2-hydr0xy-3 -i.propylaminopropane,

1-(Z-ethylthiophenoxy)-2-hydroxy-3-t.butylaminopropane,

1- 2-n.propylthiophenoxy) -2-hydroxy-3-t.butylaminopropane,

1 (2 n.propylthiophenoxy) 2 hydroxy 3 l-methyl-3-phenylpropylamino)-propane,

1 (2 secbutylthiophenoxy) 2 hydroxy 3 allylaminopropane,

1 (2 -t.butylthiophenoxy) 2 hydroxy 3 cyclopentylaminopropane,

1 (2 methylthiophenoxy) 2 hydroxy 3 cyclohexylaminopropane,

1 (2 methylthiophenoxy) 2 hydroxy 3 cyclopropylaminopropane,

1 (2 ethylthiophenoxy) 2 hydroxy 3 hexinyl-l aminopropane,

1 (2 sec.butylthiophenoxy) 2 hydroxy 3 benzylamino-propane,

and moreover salts of these compounds with pharmaceutically acceptableacids.

Suitable acids with which the compounds according to the invention canform salts are, for example, hydrochloric acid, sulphuric acid,hydrobromic acid, phosphoric acid, sulphaminic acid, tartaric acid,citric acid, oxalic acid and acetic acid.

The fi-sympatholytical activity of the compounds according to theinvention was assessed by tests on an isolated cavia atrium preparation,suspended in a Ringer solution and connected with a frequency counter.By adding N-isopropylnoradrenaline, this preparation exhibits anincrease in frequency. It has been checked to what extent this increasein frequency can be counteracted by administering a compound accordingto the invention prior to the N-isopropylnoradrenaline.

It has been found from said test that the compounds according to theinvention have a much stronger ,8- sympatholytical activity than thecompounds described in said Irish patent application. It has been found,for example, that 1 (Z-methylthiophenoxy) 2 hydroxy-3-i.propylaminopropane has a ten times stronger effect than 1(3-chlorophenoxy) 2 hydroxy 3 i.propylaminopropane, a compound qualifiedin said Irish patent application as being the most active compound.

With an anaesthetized dog also it is found that the increase in heartfrequency and the reduction of blood pressure involved in,B-sympathicomimetica are obviated, if an infusion of a compoundaccording to the invention is administered prior to theB-sympathicomimeticum.

This experiment also showed that I-(Z-methylthiophenoxy) 2hydroxy-3-i.propylaminopropane was considerably more active thanl-(3-chlorophenoxy)2- hydroxy-3-i.propylaminopropane.

The compounds according to the invention may be produced by severaldifierent methods.

Thus the compounds may be produced by reacting a compound of the FormulaIII:

wherein R has the same meaning as in Formula II and M is a hydrogen atomor an alkaline metal, with a compound of the Formula IV:

wherein R has the same meaning as in Formula II, R is a Hal- CHz-CH, ora052-7013.

group, wherein Hal is a halogen atom and R is a hydrogen atom or abenzyLgroup, the benzyl group, if any, being separated from the reactionproduct.

This reaction is preferably carried out in a solvent such as an alcohol,for example ethanol, dioxane, dimethylformamide and water.

The benzyl-group may be separated out in a conventional manner, forexample by the reduction with sodium in liquid ammonia or in alcohol.

The compounds of the Formula III are partly new. They may be obtained bystarting from O-mercaptaniline, which is alkylated with an alkyl-halide,for example the iodide or bromide, the reaction product being convertedvia the diazonium compound into the corresponding phenol.

The compounds of the Fomula IV may be obtained by known methods. Forexample, a 'l,3-dihalogen-propanol- 2 or epihalogen-hydrine may bereacted with an amine of the Formula V:

wherein R and R have the same meaning as in Formula IV. By classicalmethods, for example by means of a strong liquor, the epoxide can beobtained from the resultant halogen hydrine.

A further method of producing compounds of the Formula II consists inthat a compound of the Formula wherein R has the same meaning as inFormula II and R is a CH2CH, a HaICI-I2-CH- or an RflOOOCH-gl0ll1),

\C OH (I)H Hal a halogen atom and R an alkyl or aralkyl group, with anamine of the Formula V, an amide group, if any, being reduced and thebenzyl-group, if any, being separated out of the reaction product in themanner described above.

In this reaction for example the amine may be used as a solvent. As analternative, a polar solvent, for example ethanol, may the added.

The halogen hydrines of the Formula VI may be obtained by reacting acompound of the, Formula III with an epihalogen hydrine, for exampleepichlorohydrine. The epoxides of the Formula VI may be produced in theconventional manner, for example, from the aforesaid halogen hydrines ofthe Formula VI.

The a-hydroxy-carboxylic acid esters of the Formula VI may be producedby reacting a phenol of the Formula III in a suitable solvent, forexample, ethanol, with an a-hydroxy-B-halogen-propionic acid ester.

Compounds according to the invention may furthermore be produced byalkylating, if desired by reduction, a compound of the Formula VII OH sR;

wherein R has the same meaning as in Formula II and R is a hydrogen atomor a benzyl group and by separating out the benzyl group, if any, afterbonding.

The alkylation may be carried out with a compound of the Formula VIII:

wherein X is a Hal CH -group, a

group, R g a group like R but having one C-atom less and Hal is ahalogen atom, while if X is a i i? H Hal-C-or a CO C-R group, thebonding product is reduced. This reduction may be carried out with ahydride, for example sodium boron hydride, lithium-aluminum hydride anddi-iso- 'butylaluminum-hydride.

It is furthermore possible to carry out the reaction with a reagent ofthe Formula IX:

R/lz o-o wherein R" and R" together with the carbon atom ot the carbonylgroup, form a substituent of the group R of the Formula II. If thisagent is used, the starting material must be a compound of Formula VII,wherein R is a hydrogen atom and the coupling product is reduced with ahydride, for example, sodium boron hydride, lithium-aluminum hydride anddiisobutyl-aluminum hydride.

The compounds of Formula II may also be obtained by reducing a compoundof the Formula X I 0 R4 1 SR1 wherein R R and R have the aforesaidmeanings and by separating out the benzyl-group, if any. The reductionis preferably carried out with a hydride, for example, sodium-boronhydride, lithium-aluminum-hydride, diisobutyl-aluminum hydride. Thecompound of the Formula X may be produced by coupling a compound of theFormula III with an 1-3-dihalogen acetone, for example1,3-dichloroacetone to a compound of the Formula XI.

l SR

which substance is then converted in a solvent, for example, benzene,ethanol with an amine of the Formula V; heating may be applied to obtaincomplete reaction.

The compounds of the Formula II may furthermore be produced by reducinga compound of the Formula XII OH NHz SR1 Compounds of the Formula XIIImay be produced in a conventional manner for example by the addition ofa compound of the Formula III to the amide of 2,3-epoxypropionic acid.

The compounds according to the invention may be processed byconventional methods to obtain pharmaceutical preparations by mixing ordissolving them with or in pharmaceutically acceptable solid or liquidcarriers.

Suitable pharmaceutical preparations among others are tablets, dragees,powders, aqueous or oil-like solutions, suspensions and emulsions bothfor oral and parenteral administration, suppositories and capsules.

Carriers that may be used successfully are, for example, water,glycerine, chalk, calcium phophate, lactic sugar, powder sugar,(saccharose), calcium carbonate.

Tablets and dragees may contain swelling agents for easy dissociation ofthe preparation in water. Suitable material for swelling agents arepotato starch, maize starch, arrowroot (Amylum marantae), carboxymethylcellulose, gelatine and acasia gum. Lubricants are for example talcum,magnesium and calcium stearates and stearic acid.

Oral preparations may contain, in addition, flavoring substances such assugar or vanilla extract.

The preparations may furthermore contain preserving agents such aspropyl p-hydroxybenzoate and benzylalcohol, as well as surface-activesubstances such as mono-, diand triesters of higher fatty acids.

Our invention will now be more fully described with reference to thefollowing examples:

Injection liquid 1 (2-methylthiophenoxy) 2 hydroxy 3-i.propy1-aminopropane Suppositoria mass 1500 EXAMPLES OF PRODUCING THE COMPOUNDS1a) 1,2-epoxy-3-('2-methylthiophenoxy) -propane 11.92 g. (0.085 mol) ofZ-methylthiophenol was dissolved in a solution of 5.4 g. (0.134 mol) ofNaCH in ml. of water and at a temperature below 20 C., 15.7 g. (13.4ml.=0.17 mol) of epichlorohydrine was added in drops. The mixture wasthen stirred for one night at room temperature. The layers wereseparated and the aqueous layer was shaken three times with 30 mls. ofchloroform. The organic layers were collected and washed with water.After drying on sodium sulphate the solvent was evaporated and theresidue was distilled in vacuo.

The main fraction had a Weight of 1.96 g. and distilled between 106 C.and 108 C. at 0.20 mm.

(1b) 1(2-methylthiophenoxy)-2-hydroxy-3-isopropylaminopropanehydrochloride1.96 g. (0.010 mol) of 1,2-epoxy-3-(2-methylthiophenoxy)-propane wasdissolved in 7.5 ml. of ethanol, after which 1.2 g. (0.021 mol) ofisopropylamino in 1.2 ml. of water was added. The mixture was heated at60 for two hours. After termination of the reaction the solvent and theexcess quantity of isopropylamine was evaporated in vacuo. Melting pointof the base 87.5- 90.5 C. (after crystallization from ligroine). Thebase was dissolved in absolute ethanol and just acidified with 4 Nalcoholic hydrochloride acid. The solution was diluted with a luteether. A substance having a melting point of 1l7123 "C. crystallizedout. After one recrystallization from alcohol-ether: melting point 127C.

(2 1- Z-methylthiophenoxy) -2-hydroxy-3-t.butylaminopropanehydrochloride In the manner described in Example 1bt.butylamine was used instead of isopropylamine to obtain ahydrochloride; melting point 94-96" C.

(3 l-(Z-methylthiophenoxy)-2-hydroxy-3-1-methylphenylpropylaminopropane-hydrochlorideIn the manner described in Example 1b 1-methyl-3- phenylpropylamine wasused instead of isopropylamine to obtain a hydrochloride having amelting point of 121- 127 C.

(4)1-(2-methylthiophenoxy)-2-hydroxy-3-cyclopentylaminopropanehydrochlorideIn the same manner as described in Example 1b cyclopentylamine insteadof isopropylamine yielded a hydrochloride having a melting point of153156 C.

7 1- 2-methylthiophenoxy -2-hydroxy-2- allylaminopropane-hydrochlorideIn the same manner as described in Example 1b alkylamine instead ofisopropylamine was used to obtain a hydrochloride having a melting pointof l04-105 C.

( 6a) 1,2-epoxy-3-(Z-ethylthiophenoxy) -propane To 8.3 g. (0.053 mol) ofO-ethylthiophenol was added 20.0 g. (0.215 mol) of epichlorohydrine and0.07 ml. of piperidine. The mixture was heated on'a steam bath for onenight. After the excess quantity of epichlorohydrine and the piperidinewere removed, the residue was distilled in vacuo.

Boiling point l30-133 C./0.4 mm.

(6b) 1-(2-ethylthiophenoxy) -2-hydroxy-3.i.propylaminopropanehydrochloride 4.29 g. (-0.02 mol) of1,2-epoxy-3-(Z-ethylthiophenoxy)-propane was dissolved in rnls. ofethanol, to which was added a cooled solution of 3.5 g. (0.06 mol) isisopropylamine in 3.8 ml. of water. The mixture was heated at 37 for onehour and then for one night at 55 C.

The solution was evaporated to dryness in vacuo and dissolved twice inbenzene and again evaporated to dryness.

The residue, 5.5 gs. of oil, was crystallized from ethylacetatepetroleum ether 4060. The substance was then dissolved in 14 mls. ofethanol, 2.5 mls. of 4.2 N alcoholic HCl and 150 mls. of dry ether wereadded to this solution.

A crystalline precipitate was obtained, filtered and Washed with ether.After recrystallization from ethanolether, the substance was dried in avacuum exsiccator.

Melting point 110.5112.5 C.

What we claim is:

1. A pharmaceutical composition comprising in unit dosage form acompound selected from the group consisting of a base of the formula OHH SR1 wherein R is alkyl of 1 to 4 carbon atoms inclusive and R is amember selected from the group consisting of alkyl of 1 to 12 carbonatoms inclusive, allyl, vinyl, pentenyl, decenyl, propinyl, ethinyl,hexinyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl and aralkyl of7 to 12 carbon atoms inclusive and the pharmaceutically acceptable acidaddition salts thereof in an amount sufficiently large to cause aB-adrenergic blocking activity in humans and a pharmaceuticallyacceptable carrier therefor.

2. The pharmaceutical composition of claim 1 wherein the compound is1-(2-methylthiophenoxy)-2-hydroxy-3-i. propylaminopropane-hydrochloride.

3. The pharmaceutical composition of claim 1 wherein the compound isI-(Z-methylthiophenoxy)-2-hydroxy-3- t.butylaminopropane-hydrochloride.

4. The pharmaceutical composition of claim 1 wherein the compound is1-(2-methylthi0phenoxy)-2-hydroxy-3- 1-methyl-3-phenylpropylamino-propane-hydrochloride.

5. The pharmaceutical composition of claim 1 wherein the compound is1-(2-methylthiophenoxy)-2-hydroxy-3-cyclopentylaminopropane-hydrochloride.

6. The pharmaceutical composition of claim 1 wherein the compound isl-(2-methylthiophenoxy)-2-hydroxy-3- allylaminopropane-hydrochloride.

7. The pharmaceutical composition of claim 1 wherein the compound is1-(2-ethylthiophenoxy)-2-hydroxy-3-i. propylaminopropane-hydrochloride.

8. A method of treating a human for fi-syrnpathomimetic disturbancescomprising administering to said human a daily dose of about 29 to 400mg. of a compound selected from the group consisting of a base of thefor- I OH H wherein R is alkyl of 1 to 4 carbon atoms inclusive and R isa member selected from the group consisting of alkyl of 1 to 12 carbonatoms inclusive, alkenyl of 2 to 12 carbon atoms inclusive, alkinyl of 2to 12 carbon atoms inclusive, cycloalkyl of 2 to 12 carbon atomsinclusive and aralkyl of 7 to 12 carbon atoms inclusive and thepharmaceutically acceptable acid addition salts thereof.

9. The method of claim 8 wherein the compound is 1-(2methylthiophenoxy)-2-hydroxy-3-i.propylaminopropane-hydrochloride.

10. The method of claim 8 wherein the compound is 1-(2methylthiophenoxy)-2-hydroxy-3-t.butylaminopropane-hydrochloride.

11. The method of claim 8 wherein the compound is 1-(2methylthiophenoxy) -2-hydroxy-3-( 1-methy1-3-phen ylpropylamino)-propane-hydrochloride.

12. The method of claim 8 wherein the compound is 1 2-metl1ylthiophenoxy-2-hydr0xy-3 -allylaminoprop anehydrochloride.

13. The method of claim 8 wherein the compound is 1- (2methylthiophenoxy 2-hydroxy-3-cyclopentylaminopropane-hydrochloride.

14. The method of claim 8 wherein the compound is 1-(2-ethylthiophenoxy)2 hydroXy-3-i.propylaminopropane-hydrochloride.

No references cited.

STANLEY J. FRIEDMAN, Primary Examiner

